The structural element that is common to all members of the family of the G-protein-coupled receptors (GPCR) is the presence of seven transmembrane-alpha-helical segments that are connected to one another by alternating intracellular and extracellular loops, whereby the amino-terminus is found on the extracellular side, and the carboxy-terminus is found on the intracellular side. The family of GPCRs can be divided into several subfamilies (essentially families A, B and C) with additional sequence homologies within these subfamilies. Since GPCRs are involved primarily in signal reception and transmission, a number of physiological functions are influenced by them. GPCR ligands are therefore potentially suitable as medications for therapy and prevention of a large number of pathologic conditions. A small overview on diseases that can be treated with GPCR ligands is provided in Table I in S. Wilson et al., Pharmaceutical News 2000, 7(3).
The majority of known GPCR ligands are of peptidic structure. Peptidic receptor ligands, however, often have some significant drawbacks, such as, for example, low bioavailability and metabolic instability. Therefore, in recent years, an intensified search has been run for ligands in the form of small, non-peptidic molecules. So-called “privileged structures” play a special role in the search for new, non-peptidic receptor ligands. These “privileged structures” are those basic molecular structures that prepare ligands for a number of different receptors. The term “privileged structures” was used for the first time by Evans et al. in connection with the benzodiazepine-based CCK (cholecystokinin)-A antagonists from the natural substance Asperlicin (B. E. Evans et al., J. Med. Chem. 1988, 31, 2235). For proteases, it has already been known for a long time, for example, that certain structure classes can be used as inhibitors for various enzymes. While in the past primarily mechanism-based inhibitors were described for various proteases, more recently, however, and more and more often, examples of compounds that readily fit into the active binding regions of various enzymes because of their three-dimensional structure have been found (cf. M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A. S. Ripka et al., ibid., 441). Such “privileged structures” were also already described for GPCRs. Examples to this end, in addition to the above-mentioned benzodiazepines, are also peptoids, 4-substituted 4-arylpiperidines, but also special β-Turn mimetic agents that are made rigid (B. A. Bunin et al., Ann. Rep. Med. Chem. 1999, 34, 267; R. N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G. C B. Harriman, Tetrahedron Lett. 2000, 41, 8853). A survey to this end is found in A. A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. With the tetrahydrocarbazole derivatives according to this invention, another class of “privileged structures” is made available for GPCRs.
Although this invention generally prepares ligands for GPCRs, the compounds that are prepared by this invention are especially suitable as ligands for a certain representative of the class of GPCRs, namely the gonadotropin-releasing hormone receptor (GnRH receptor). The GnRH receptor can be classified in subfamily A of the GPCRs (cf. U. Gether et al., Endocrine Reviews 2000, 21(1), 90).
GnRH is a hormone that mainly, but not exclusively, is synthesized in mammals by the nerve cells of the hypothalamus, is transported via the portal veins into the pituitary gland and is released in a regulated manner to the gonadotropic cells. By interaction with its receptor that has seven transmembrane domains, GnRH stimulates the production and the release of gonadotropic hormones by means of the second messenger inositol-1,4,5-triphosphate and Ca2+ ions. The gonadotropin-luteinizing hormone (LH) that is released by GnRH and the follicle-stimulating hormone (FSH) stimulate the production of sex steroids and the gamete maturation in both sexes. In addition to GnRH (also referred to as GnRH1), there are two other forms of GnRH, namely GnRH2 and 3.
The GnRH receptor is used as a pharmacological target in a number of diseases, which are dependent on a functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. In the case of these diseases, GnRH superagonists or GnRH antagonists can be used successfully. In particular, the male birth control in combination with a substitution dose of androgens forms a possible further indication.
An advantage of GnRH antagonists in comparison to GnRH superagonists is their immediate effectiveness in the blocking of the gonadotropin secretion. Superagonists initially produce an overstimulation of the hypophysis, which results in increased gonadotropin and sex steroid releases. This hormonal reaction is only completed after a certain delay based on the desensitization and downward-adjustment of the GnRH receptor concentrations. Therefore, GnRH superagonists, both alone and in combination with testosterone, may not be able to suppress sperm production in males effectively and thus are not suitable for male birth control. In contrast to this, peptidic GnRH antagonists, especially in combination with a substitution dose of androgen, are able to bring about a significant oligozoospermia in humans.
Peptidic GnRH antagonists, however, have a number of drawbacks. They have a considerably lower effectiveness as superagonists and consequently have to be administered at considerably higher dosages. Their oral bio-availability is also low, so that they have to be administered by injection. Repeated injections lead in turn to a reduction in compliance. Moreover, the synthesis of peptidic GnRH antagonists in comparison to non-peptidic compounds is costly and labor-intensive.
Quinoline derivatives as non-peptidic GnRH antagonists are disclosed in, for example, WO 97/14682. To date, however, it was not possible to market any non-peptidic GnRH antagonists.